Abstract Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence, for example, could yield treatments for managing COC dependence. Obesity is also a significant public health concern. While obesity and COC dependence are typically considered distinct clinical entities, both involve perturbations of central biogenic amine systems. The obesity epidemic has spurred development of medications to promote weight loss. The Food and Drug Administration (FDA) recently approved a combination of topiramate (TOP) and phentermine (PHEN) for obesity. The overarching goal of this application is to demonstrate the initial efficacy, safety, and tolerability of TOP-PHEN combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking, COC-dependent participants will be randomized to different TOP maintenance doses (i.e., TOP is a between-subject factor). Participants (N=12) in each TOP cohort will be maintained concurrently on PHEN (i.e., PHEN is a within-subject factor). The reinforcing effects of COC will be determined after participants in each TOP cohort are maintained for 7 days on each PHEN dose (i.e., COC is a within-subject factor). COC (4 [placebo], 40, 80 mg) will be tested with each dose combination of TOP (0, 100, 200 mg/day) and PHEN (0, 15, 30 mg/day). The proposed study will therefore identify the optimal TOP-PHEN dose combination that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses of a novel drug combination, TOP and PHEN, for COC dependence, which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposal include: 1) testing a drug combination effective for a disorder, obesity, that shares neurobiological and behavioral substrates with COC addiction; 2) the use of drug self-administration procedures; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of TOP-PHEN combinations for COC addiction; 4) demonstrating the initial efficacy of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly; 5) facilitating communications between scientists studying distinct clinical entities (e.g., obesity and COC addiction); and 6) spurring sponsor interest in addiction pharmacotherapy because demonstrating the efficacy of the TOP-PHEN combination would support a novel indication for this product in a new population and extend patent life. The proposed project will shift the current research paradigm in pharmacotherapy development and have a significant impact on COC abuse treatment.